The present invention relates to a process for preparing cis-2,6-dimethylpiperazine by reacting diisopropanolamine or 1,2-diaminopropane with ammonia and hydrogen in the presence of a catalyst.
Substituted piperazines are useful intermediates for the synthesis of rubber processing aids, in particular of vulcanization accelerators, and for the synthesis of crop protection agents and pharmacologically active compounds. Cis-2,6-dimethylpiperazine, for example, is an important starting material for the synthesis of certain antibacterial quinolone-carboxylic acid derivatives such as sparfloxacin (Arzneim.-Forsch., 41, 744-746 (1991)). Accordingly, the preparation of substituted piperazines, particularly cis-2,6-dimethylpiperazine, is of increasing importance.
British Patent 1,295,784 describes a process for preparing N-(2-aminoethyl)piperazine by cyclization of aminoethanol in aqueous medium in the presence of ammonia, hydrogen, and a catalyst. When carrying out this process, it is essential that a fraction of the reaction mixture is, after distillative removal of as much of the desired N-(2-aminoethyl)piperazine as is possible, recycled into the reaction. This measure allows the N-(2-aminoethyl)piperazine yield to be increased considerably.
U.S. Pat. No. 3,692,789 likewise discloses a process for preparing N-(2-aminoethyl)piperazine. In the presence of ammonia, hydrogen, and a hydrogenation catalyst, N-(hydroxyethyl)diethylenetriamine is cyclized to give N-(2-aminoethyl)piperazine.
According to U.S. Pat. No. 3,112,318, the synthesis of piperazine from aminoethanol is carried out in the presence of ammonia, hydrogen, and a hydrogenation catalyst. In this process, it is important to operate in the absence of water. By-products formed in the reaction are ethylenediamine and N-(2-aminoethyl)piperazine.
In contrast to the piperazine mentioned above, as well as to nitrogen-substituted piperazines, 2,6-dimethylpiperazine has two asymmetric carbon atoms in positions 2 and 6. Accordingly, two stereo-isomers, trans- and cis-2,6-dimethylpiperazine, exist, both of which can in principle be formed in synthesis reactions.
U.S. Pat. No. 2,525,223 discloses a process for preparing mono-N-alkylpiperazines by reacting dialkanolamines in the form of diethanolamine or its alkyl derivatives with a primary alkylamine in the presence of a catalyst, such as, for example, Raney nickel. The experiments described in the patent are exclusively reactions of diethanolamine with methyl-, ethyl-, or isopropylamine to give mono-N-(methyl-, ethyl-, or isopropyl)-piperazine. The conversions obtained in these reactions are very low, being at most 34%. With respect to di(2-hydroxypropyl)amine, which is mentioned in principle as a starting material, no further statements, particularly about which products and stereoisomers are formed during the reaction, are made.
Japanese Laid-Open Publication Hei 8-34773 discloses a process for preparing cis-2,6-dimethylpiperazine starting from diisopropanolamine. This diisopropanolamine is pure diisopropanolamine of the structure HN(CH.sub.2 CH(OH)CH.sub.3).sub.2 (i.e., di(2-hydroxypropyl)amine) since, in the course of the reaction, only the formation of cis- and trans-2,6-dimethylpiperazine is reported. If, in addition to the HN--(CH.sub.2 --CH(OH)CH.sub.3).sub.2, HN(CH(CH.sub.3)--CH.sub.2 OH)(CH.sub.2 CH(OH)CH.sub.3) were also present, cis- and trans-2,5-dimethylpiperazine would also have to have been formed as products of the cyclization reaction. The pure uniform diisopropanolamine is initially reacted in an organic solvent in the presence of a catalyst with ammonia and hydrogen. Preferred organic solvents are aromatic hydrocarbons, such as benzene, toluene, or xylene. The mixture of cis-2,6- and trans-2,6-dimethylpiperazine formed during the cyclization in the organic solvent is initially separated from the catalyst by filtration, then freed from water by azeotropic distillation and, after further addition of organic solvent, subjected to crystallization. The crystallized cis-2,6-dimethylpiperazine is separated. Some of the trans-2,6-dimethylpiperazine that remains in the reaction mixture can subsequently be isomerized in the presence of a catalyst at a temperature of at least 180.degree. C. to give cis-2,6-dimethyl-piperazine, with the overall yield of cis-2,6-dimethylpiperazine thereby being increased. The presence of the organic solvent is emphasized as being decisive for the selectivity of the primary cyclization for the cis-2,6-dimethylpiperazine. Thus, in the cyclization of diisopropanolamine of the formula HN(CH.sub.2 CH(OH)CH.sub.3).sub.2 with Raney nickel in the presence of toluene, a selectivity of 81 to 82% is achieved. In contrast, in the presence of water instead of toluene, a selectivity of only 72% for the cis-2,6-di-methylpiperazine is achieved.
U.S. Pat. No. 2,911,407 describes another process for preparing 2,6-dimethylpiperazine with conversions of an order of magnitude of 70%. To this end, di(2-hydroxypropyl)amine is reacted under pressure with ammonia in the presence of a nickel- or cobalt-containing hydrogenation/dehydrogenation catalyst, using at least 1 mol of ammonia per mole of di(2-hydroxypropyl)amine. Preferred catalysts are Raney nickel and Raney cobalt. U.S. Pat. No. 2,911,407 does not indicate whether and in what proportions the isolated 2,6-dimethylpiperazine contains the two cis- and trans-stereoisomers. Moreover, the 2,6-dimethylpiperazine is not separated into the two stereoisomers.
British Patent 902,570 discloses a process for preparing C-alkylsubstituted piperazines from di(2-hydroxyalkyl)amines having at least one secondary hydroxyl group. According to the description and the Examples of GB 902,570, these di(2-hydroxyalkyl)amines, such as diisopropanolamine in the form of di(2-hydroxypropyl)amine, 1-(2-hydroxyethylamino)-2-propanol, or 3,3-imino-di-2-butanol, are always employed in pure form and not as mixtures of different isomers. The catalyst used in the reaction must comprise at least one metal or metal oxide from the group consisting of nickel, copper, and cobalt. Additionally, it may comprise small amounts of chromium oxide, molybdenum oxide, manganese oxide, thorium oxide, or mixtures thereof as promoters. Reaction of di(2-hydroxypropyl)amine with ammonia and hydrogen in the presence of a hydrogenation catalyst made of nickel, copper, and chromium oxides gives 2,6-dimethylpiperazine, the conversion obtained in Example II being above 90% and the yield of 2,6-dimethylpiperazine being 74.3%. However, like the above-mentioned U.S. Pat. No. 2,911,407, GB 902,570 contains no statements about whether and in what proportions the isolated 2,6-dimethylpiperazine is composed of the two cis- and trans-stereoisomers, and the 2,6-dimethylpiperazine is not separated into the two stereoisomers.
In the synthesis of 2,6-dimethylpiperazine, each of the above-mentioned processes employs pure substances such as di-(2-hydroxypropyl)amine, for which isolation is always complicated, as starting materials. Moreover, little is known about the targeted and selective preparation of cis-2,6-dimethylpiperazine and only a few options are available.
Accordingly, it was an object of the present invention to provide a process that, using more easily obtainable starting materials, makes it possible to obtain the pure cis-2,6-dimethylpiperazine stereoisomer in a selective preparation.